We have demonstrated that the in a rat model. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby the IGF-l/Akt/mTOR/p70S6 kinase signaling pathway can lead to apoptosis and proliferation, cyst formation and renal failure in PKD. Novel preliminary data demonstrates activation of Akt and rapamycin-induced inhibition of p70S6K activity in PKD kidneys. Complementary studies will be performed in Han:SPRD rats, PKD2WS25/- and cpk mouse models of PKD and mice with a functional floxed allele of Pkd1. Specific Aim 1 focuses on in vivo studies using mTOR inhibitors. The effect of mTOR inhibition on apoptosis and proliferation, cyst formation and renal function will test the potential for clinical application. In Specific Aim 2, we shall investigate the IGF-l/Akt/mTOR/p70S6 kinase signaling pathway in PKD. Our preliminary data demonstrate that rapamycin decreases caspase-3 activation and apoptosis in PKD. Preliminary data also demonstrate that HIF-1a is increased in PKD kidneys. mTOR functions as a positive regulator of HIF-1- dependent responses and rapamycin is known to inhibit HIF-1a. We propose that HIF-1 is proapoptotic in polycystic kidneys and that rapamycin inhibits HIF-1 induced caspase-3 activation and apoptosis. In Specific Aim#3, we shall determine the time course of HIF-1a activation and the effect of rapamycin on HIF-1a, caspase-3 and apoptosis. The relevance of these studies to clinical ADPKD is substantial and the results should provide leads to altering the course of ADPKD. This is particularly true because of the current availability of mTOR antagonists e.g. rapamycin and its analogs and their proven in vivo beneficial effect as immunosuppressive drugs and cancer treatments.